The present invention relates to new 19-Nor steroids having a thiocarbonated chain in position 11beta, their preparation process and the intermediates of this process, their use as medicaments and the pharmaceutical compositions containing them.
A subject of the invention is the compounds of formula (I): 
in which R17 and Rxe2x80x217 are such that:
either R17 and Rxe2x80x217 together form a ketone function, an oxime function, a hydrazono function or a methylene radical,
or R17 is a hydroxyl radical, a hydroxymethyl radical or an acyloxy radical having at most 12 carbon atoms and Rxe2x80x217 represents a hydrogen atom, an alkyl, alkenyl or alkynyl radical having at most 8 carbon atoms, each of these substituents being optionally substituted,
R3 represents a hydrogen atom, a linear or branched alkyl radical or a cyclic alkyl radical having at most 8 carbon atoms or an acyl radical having at most 12 carbon atoms,
R16 represents a hydrogen atom, a halogen atom or an alkyl radical having at most 8 carbon atoms, m has the value 0, 1 or 2, X, Y and Z are such that:
X represents a methylene radical, an arylene or arylenoxy group, having at most 10 carbon atoms linked to the steroid by a carbon atom,
Y represents a saturated or unsaturated, linear or branched aliphatic chain, containing 1 to 18 carbon atoms, optionally interrupted by an oxygen atom,
Z represents:
a linear or branched alkyl radical, containing 1 to 8 carbon atoms and optionally substituted, or an aryl or arylalkyl radical, each of these radicals being optionally substituted, in which the alkyl radical contains at most 6 carbon atoms and the aryl radical represents a monocyclic radical containing 5 or 6 members or a radical constituted by condensed rings containing 8 to 10 members, these radicals optionally containing one or more heteroatoms chosen from oxygen, nitrogen or sulphur atoms,
the alkyl radicals that can be represented by Rxe2x80x217 and Z, the alkenyl or alkynyl radicals that can be represented by Rxe2x80x217 and the aryl or arylalkyl radicals that can be represented by Z being optionally substituted by one or more radicals chosen from the following radicals:
halogens,
amino, alkylamino or dialkylamino in which the alkyl radical or radicals have 1 to 4 carbon atoms,
hydroxyl,
free, esterified or salified carboxy,
alkyl having 1 to 8 carbon atoms, optionally substituted by one or more halogen atoms,
oxo, cyano, nitro, formyl,
acyl or acyloxy having at most 12 carbon atoms,
alkoxy or alkylthio having 1 to 4 carbon atoms,
carbamoyl,
alkenyl or alkynyl having at most 4 carbon atoms,
aryl as defined above, and the addition salts of the above.
By acyloxy radical can be meant in particular the derivative of a saturated or unsaturated aliphatic or cycloaliphatic acid and notably an alkanoic acid such as, for example, acetic, propionic, butyric or isobutyric, valeric or undecylic acid, a hydroxyalkanoic acid such as, for example, hydroxyacetic acid; a cycloalkylcarboxylic or cycloalkylalkanoic acid such as, for example, cyclopropyl, cyclopentyl or cyclohexylcarboxylic, cyclopentyl or cyclohexyl acetic or propionic acid, a benzoic acid, a salicylic acid or a phenylalkanoic acid such as phenyl acetic or phenyl propionic acid, an amino acid such as diethylamino acetic or aspartic acid, formic acid or an optionally salified diacid, such as, for example, butanedioic acid or the monosodium salt of the latter. It is preferably the derivative of acetic, propionic or butyric acid.
By acyl radical is meant the radicals corresponding to the previous acyloxy radicals.
By alkyl radical can be meant one of the following radicals: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-pentyl, n-hexyl, 2-methyl pentyl, 2,3-dimethyl butyl, n-heptyl, 2-methyl hexyl, 2,2-dimethyl pentyl, 3,3-dimethyl pentyl, 3-ethylpentyl, n-octyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 3-methyl 3-ethyl pentyl.
It is preferably the methyl radical.
When R3 represents a cyclic alkyl radical, it can be a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radical. It is preferably the cyclopentyl radical.
By alkoxy radical, can notably be meant the methoxy, ethoxy, propyloxy, butyloxy radical and by alkylthio radical, can notably be meant the methylthio, ethylthio, propylthio or butylthio radicals.
By alkenyl radical, can be meant a vinyl, propenyl, isopropenyl, allyl, 2-methyl allyl, butenyl or isobutenyl radical. It is preferably the vinyl or propenyl radical.
By alkynyl radical, can be meant the ethynyl, propynyl, propargyl, butynyl or isobutynyl radical. It is preferably the ethynyl or propynyl radical.
When R16 represents a halogen atom, it can be a bromine, chlorine, fluorine or iodine atom; it is preferably a bromine atom.
When X represents an arylene group, it is preferably the phenylene radical.
When X represents an arylenoxy group, it is preferably the phenylenoxy radical.
When Y represents a saturated or unsaturated, linear or branched aliphatic chain, it can be one of the following radicals: methylene, ethylene, propylene, isopropylene, butylene, isobutylene, or tert-butylene, n-pentylene, n-hexylene, 2-methyl pentylene, 2,3-dimethyl butylene, n-heptylene, 2-methyl hexylene, 2,2-dimethyl pentylene, 3,3-dimethyl pentylene, 3-ethyl-pentylene, n-octylene, 2,2-dimethyl hexylene, 3,3-dimethyl hexylene, 3-methyl 3-ethyl pentylene, nonylene, 2,4-dimethyl heptylene, n-decylene, n-undecylene, n-dodecylene, n-tridecylene, n-tetradecylene, n-pentadecylene, n-hexadecylene, n-heptadecylene or n-octadecylene, preferably n-pentylene, n-hexylene, n-heptylene, n-octylene or n-nonylene.
It can also be vinylene, isopropenylene, allylene, 2-methyl allylene, isobutenylene, butenylene, pentenylene, hexenylene, heptenylene or octenylene radicals, preferably the hexenylene radical.
It can also be ethynylene, propynylene, propargenylene, butynylene, isobutynylene, pentynylene, hexynylene, heptynylene or octenylene radicals, preferably the propynylene, hexynylene or octynylene radicals.
It can be a chain interrupted by an oxygen atom, for example, an oxapolymethylene radical, preferably the oxy diethylene radical.
When Z represents a linear or branched alkyl radical, it can be the radicals indicated above, preferably propyl, butyl, n-pentyl.
When Z represents an arylalkyl group, the alkyl radical can be one of the radicals defined above, notably a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-pentyl or n-hexyl radical, it is preferably the methyl or ethyl radical.
By aryl group which can be contained in an arylalkyl group, is meant:
a carbocyclic monocyclic radical, for example the phenyl radical,
a heterocyclic monocyclic radical, for example the following radicals: thienyl, furyl, pyrannyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazannyl, pyrrolinyl, imidazolinyl, pyrazolinyl, thiazolinyl, triazolyl, tetrazolyl, as well as the isomers of position of the heteroatom or heteroatoms that these radicals can contain,
a radical constituted by carbocyclic condensed rings, for example, the naphthyl radical or phenanthrenyl radical,
a radical constituted by heterocyclic condensed rings, for example, benzofurannyl, benzothienyl, benzimidazolyl, benzothiazolyl, naphtho[2,3-b]thienyl, thianthrenyl, isobenzofurannyl, chromenyl, xanthenyl, phenoxathiinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, beta-carbolinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, indolinyl, isoindolinyl, imidazopyridyl, imidazopyrimidinyl or also the condensed polycyclic systems constituted by heterocyclic monocyclics, as defined, for example, above, such as for example furo[2,3-b]pyrrole or thieno[2,3-b]furan.
When Z represents an aryl or arylalkyl group, there can be mentioned as examples of such an aryl radical, in particular, the following radicals: phenyl, furyl such as 2-furyl, imidazolyl such as 2-imidazolyl, pyridyl such as 2-pyridyl, 3-pyridyl or 4-pyridyl, pyrimidinyl such as pyrimid-2-yl, thiazolyl such as thiazol-2-yl, thiazolinyl such as thiazolin-2-yl, triazolyl such as triazol-2-yl, tetrazolyl such as tetrazol-2-yl, benzimidazolyl such as benzimidazol-2-yl, benzothiazolyl such as benzothiazol-2-yl, purinyl such as purin-7-yl or quinolyl such as 4-quinolyl and as examples of arylalkyl radicals, there can also be mentioned in particular the methyl or ethyl radicals substituted by one of the above aryl radicals.
The expression optionally substituted applied to the alkyl radicals that can be represented by Rxe2x80x217 and Z, the alkenyl or alkynyl radicals that can be represented by Rxe2x80x217 and the aryl or arylalkyl radicals that can be represented by Z, indicates that these can be optionally substituted by one or more identical or different radicals chosen from the radicals indicated previously and in particular,
halogen: fluorine, chlorine, bromine, iodine,
amino, alkylamino such as methylamino or ethylamino, dialkylamino such as dimethylamino, diethylamino, methylethylamino,
hydroxyl,
free, esterified carboxy such as alkoxy carbonyl for example methoxy carbonyl or ethoxycarbonyl, or carboxy salified for example by a sodium or potassium atom,
alkyl having 1 to 8 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, optionally substituted by one or more halogen atoms, for example fluorine such as trifluoromethyl,
oxo, cyano, nitro, formyl,
acyl such as acetyl, propionyl, butyryl, benzoyl,
acyloxy such as acetoxy, a radical of formula xe2x80x94Oxe2x80x94COxe2x80x94(CH2)nxe2x80x94COOH in which n=1 to 5,
alkoxy such as methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy,
alkylthio such as methylthio, ethylthio, propylthio, isopropylthio, butylthio,
carbamoyl,
alkenyl such as vinyl, propenyl,
alkynyl such as ethynyl, propynyl,
aryl such as phenyl, furyl, thienyl.
As an example of such substituted radicals, there can be mentioned for example an alkyl radical substituted by one or more halogen atoms, for example, fluorine, such as the trifluoroethyl, trifluorobutyl, pentafluoropropyl, pentafluorobutyl, pentafluoropentyl, heptafluorobutyl or nonafluorobutyl radical, an alkyl radical substituted by an aryl radical, for example the phenyl radical, itself substituted by one or more halogen atoms and/or alkyl radicals substituted by one or more halogen atoms, such as pentafluorobenzyl, pentafluorophenylethyl, pentafluorophenylpropyl, 4-trifluoromethyl 2,3,5,6-tetrafluorobenzyl.
There can also be mentioned, for example, an aryl radical substituted by one or more halogen atoms, for example, chlorine such as 2,3,5,6-tetrachloro 4-pyridyl, by an amino group such as 4,6-diamino 2-pyrimidinyl, by a hydroxyl such as 2,6-dihydroxy 4-pyrimidinyl, by an esterified carboxyl for example a methoxycarbonyl such as 2-methoxycarbonyl phenyl, by an alkyl, for example a methyl such as N-methyl imidazolyl, N-methyl triazolyl or N-methyl tetrazolyl, optionally substituted by a halogen for example fluorine such as 7-(trifluoromethyl) 4-quinolyl, by an oxo group and an alkyl radical, for example, a methyl radical such as 1,3-dimethyl 2,6-dioxopurin-7-yl.
The invention naturally extends to the salts of the compounds of formula (I), such as for example, the salts formed when the compounds of formula (I) contain an amino function, with the following acids: hydrochloric, hydrobromic, nitric, sulphuric, phosphoric, acetic, formic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkanesulphonic, such as methane or ethanesulphonic, arenesulphonic, such as benzene or paratoluene sulphonic and arylcarboxylic, or when the compounds of formula (I) contain an acid function, with the salts of alkali or alkaline-earth metals or of optionally substituted ammonium.
Among the preferred compounds of formula (I) of the invention, there can be mentioned in particular the compounds in which R3 and R16 represent a hydrogen atom.
Among the preferred compounds of formula (I) of the invention, the compounds in which m=1 and those in which m=2 can be particularly mentioned.
Among the compounds of the invention, there can be mentioned in particular the compounds of formula (I), in which R17 is a hydroxyl radical and Rxe2x80x217 is a hydrogen atom or a methyl radical.
Among the compounds of the invention, there can be mentioned in particular the compounds of formula (I), in which X represents a methylene radical and Y is a saturated linear chain containing 7 to 9 carbon atoms, those in which X represents a phenylene radical and Y represents a saturated or unsaturated linear chain containing 3 to 8 carbon atoms, it being understood that, when the chain is unsaturated, it contains a vinylene or ethynylene group linked directly to the phenylene radical and those in which X represents a phenylenoxy radical and Y represents a saturated linear chain containing 4 to 7 carbon atoms, optionally interrupted by an oxygen atom. When X represents a phenylenoxy radical, Y preferably contains 5 or 6 carbon atoms.
Among the compounds of the invention, there can be mentioned especially the compounds of formula (I) in which Z represents a linear alkyl radical containing 1 to 5 carbon atoms, a trifluoroalkyl radical containing 2 to 4 carbon atoms, a pentafluoroalkyl radical containing 4 or 5 carbon atoms, a nonafluoroalkyl radical containing 1 to 4 carbon atoms,
a radical containing a substituted phenyl radical chosen from: 
xe2x80x83in which the alkyl represents an alkyl radical containing 1 to 4 carbon atoms and q represents the values 1, 2 or 3.
a radical containing a heterocycle with 5 members chosen from: 
a radical containing a heterocycle with 6 members chosen from: 
a radical containing a heterocycle with two condensed rings chosen from: 
Among the preferred values of Z, there can be mentioned more particularly the pentyl value and the pentafluoroalkyl value and in particular the pentafluoropropyl, pentafluorobutyl or pentafluoropentyl values.
Therefore, among the preferred compounds of the invention, there can be mentioned the compounds whose preparation is given hereafter in the experimental part and more particularly:
11beta-[-8-[(2-pyridinylmethyl)thio]octyl]estra-1,3,5(10)-triene-3,17beta-diol,
11beta-[4-[3-[(1-methyl 1H-imidazol-2-yl)thio]1-propynyl]phenyl]estra-1,3,5(10)-triene-3,17beta-diol,
11beta-[4-[5-[(2-furanylmethyl)thio]pentyloxy]phenyl]estra-1,3,5(10)-triene-3,17beta-diol,
11beta-[4-[5-[(2-pyridinylmethyl)sulphinyl]pentyloxy]phenyl]estra-1,3,5(10)-triene-3,17beta-diol,
11beta-[4-[5-[(3-pyridinylmethyl)sulphinyl]pentyloxy]phenyl]estra-1,3,5(10)-triene-3,17beta-diol,
11beta-[4-[6-[(4,4,5,5,5-pentafluoro pentyl)sulphinyl]hexyloxy]phenyl]estra-1,3,5(10)-triene-3,17beta-diol,
11beta-[4-[5-[(4,4,5,5,5-pentafluoropentyl)sulphinyl]pentyloxy]phenyl]estra-1,3,5(10)-triene-3,17beta-diol,
11beta-[4-[5-(pentylsulphonyl]pentyloxy]phenyl]estra-1,3,5(10)-triene-3,17beta-diol,
11beta-[4-[5-[(4,4,5,5,5-pentafluoro pentyl)sulphonyl]pentyloxy]phenyl]17alpha-methyl estra-1,3,5(10)-triene-3,17beta-diol.
Also a subject of the invention is a preparation process for the compounds of formula (I) characterized in that a compound of formula (II): 
in which:
R17a and Rxe2x80x217a have the meanings indicated previously for R17 and Rxe2x80x217 and in which the optional reactive functions are optionally protected,
X and Y have the same meaning as previously,
Rxe2x80x23 represents a hydrogen atom or a protective group of the hydroxyl function,
hal represents a halogen atom or a pseudo-halogen group such as a tosylate, is subjected to the action of a mercaptan of formula (III):
Zaxe2x80x94SHxe2x80x83xe2x80x83(III)
xe2x80x83or a salt of the latter, in which Za has the meaning indicated previously for Z in which the optional reactive functions are optionally protected, then, if appropriate, to the action of an elimination agent of the protective groups, in order to obtain the compound of formula (IA) corresponding to the product of formula (I) in which m=0, which product of formula (IA) is subjected, if desired and if necessary, to any one of the following reactions, in any order:
reduction of the ketone function which can be represented by R17 and Rxe2x80x217 together,
addition on the ketone function which can be represented by R17 and Rxe2x80x217 of a metallic complex of formula (IV):
Mxe2x88x92Rxe2x80x217axe2x80x83xe2x80x83(IV)
xe2x80x83in which M represents a metal atom and Rxe2x80x217a has the same meaning as previously, it being understood that it is not a hydrogen atom,
conversion of the ketone function which can be represented by R17 and Rxe2x80x217 together into an oxime function, into a hydrazono or methylene group,
selective acylation in position 17 when R17 is a hydroxyl,
halogenation or alkylation in position 16,
alkylation or acylation of the hydroxyl radical in position 3,
partial or total reduction of the ethynylene group, when Y represents an unsaturated chain,
oxidation of the sulphur into the sulphoxide or sulphone,
optional salification by an acid or a base.
The compounds of formula (IA) corresponding to the compounds of formula (I) in which m=0, are obtained by reacting a compound of formula (II), in which hal is for example a chlorine atom, a bromine atom or a tosylate, OR3 is a hydroxyl optionally protected for example by an acetyl, tertiobutyl or tetrahydropyranyl radical and R17a Rxe2x80x217a have reactive functions optionally protected by the usual methods, with a compound of formula (III), preferably in the form of a salt obtained by the addition, for example, of sodium carbonate, soda or sodium methylate or ethylate, the reaction being carried out in a neutral solvent, for example methanol, dimethylformamide, hexamethylphosphorotriamide (HMPT) or acetonitrile (CH3CN), by itself or in a mixture, operating, for example, at approximately 50xc2x0 C. or under reflux, if necessary in the presence of a reagent such as sodium iodide, then if appropriate, subjecting the compound obtained to the action of a deprotection agent of the reactive functions.
According to the values of the protective group Rxe2x80x23, the products of formula (IA) can represent products of formula (I).
The protective groups which can be used to protect the reactive functions, such as, for example, the amino or hydroxyl functions, are chosen from the usual groups from organic chemistry and more particularly from the chemistry of the peptides. A non-exhaustive list of these groups as well as the corresponding elimination methods can be found in the French Patent FR 2,499,995 whose content is incorporated in the present Application by way of reference. For example, the tetrahydropyrannyl or trityl radicals can be mentioned.
In a preferred embodiment of the invention:
the compounds of formula (II) containing a chain in position 11beta terminated by a halogen or a pseudohalogen such as, for example, the group xe2x80x94Oxe2x80x94SO2xe2x80x94xcfx86xe2x80x94CH3 in which "PHgr" represents a phenylene radical, as illustrated in the following examples, as well as the compounds of formula (III) mentioned below in the experimental part, can be used. In a non-exhaustive manner, the following can be mentioned: the methyl ester of 2-mercapto benzoic acid, furfurylmercaptan, 2-thiazoline-2-thiol, 2-mercapto thiazole, 2-mercapto 1-methyl imidazole, 1-methyl 5-mercapto-1,3,4-thiazole, 1-methyl 5-mercapto 1,2,3,4-tetrazole, 2-pyridinemethanethiol, 4,6-diamino pyrimidine-3-thiol, 2,3,5,6-tetrachloro pyridine-4-thiol, 2-mercapto benzothiazole, 7-trifluoromethyl 4-quinolinethiol and 4,4,5,5,5-pentafluoro-pentanethiol.
When the compound of formula (IA) contains protected reactive functions, the corresponding deprotected compound is obtained by the action of standard agents, for example, a saponification agent such as potash in an alcoholic medium or a hydrolysis agent such as hydrochloric acid. The deprotection methods which can be used are also described in the French Patent FR 2,499,995.
When the compound of formula (IA) contains a ketone function in position 17:
the corresponding hydroxylated 17beta compound is obtained for example by the action of a reducing agent such as sodium borohydride in a neutral solvent such as methanol,
the corresponding compound containing an Rxe2x80x217 radical representing an optionally substituted alkyl, alkenyl or alkynyl radical is obtained, by the addition of a compound (IV), such as, for example, a lithium complex, according to the process described in the European Patent EP 57115,
the corresponding compound containing an oxime function in position 17 is obtained, for example, by the action of hydroxylamine in the form of a salt such as the hydrochloride, in the presence of a weak base in an alcohol at reflux temperature,
the corresponding compound containing a hydrazono function in position 17 is obtained, for example by the action of a derivative of hydrazine and notably hydrazine hydrate in the presence of an acid such as paratoluenesulphonic acid,
the corresponding compound containing a methylene function in position 17 is obtained by using a Wittig reaction, for example, methyltriphenylphosphonium bromide in a basic medium.
When the compound of formula (IA) contains a hydroxyl function in position 3 or 17, the corresponding 3 or 17beta acyloxylated compound is obtained, by the action of a selective acylation agent, for example, acetic anhydride in pyridine.
When the compound of formula (IA) contains an ethynylene group, the corresponding compound having a vinyl bond or the corresponding saturated compound is obtained by the action of a partial or total reducing agent, either by using hydrogen in the presence of palladium, on activated charcoal or over barium sulphate and optionally in the presence of a base such as pyridine or quinoline, in the case of a partial reduction, or using palladium hydroxide by itself in the case of a total reduction.
The compounds containing an alkyl radical in position 16 can be obtained, for example, by the action of an alkyl halide, such as methyl iodide or ethyl iodide in the presence of a lithium complex.
The compound containing a halogen in position 16 can be obtained, for example, by the action of bromine in an acid medium notably in acetic acid or also by the action of a halogenation agent such as N-bromo or N-chloro succinimide or N-bromo or N-chloro acetamide or also tertbutyl hypochlorite.
The compounds of formula (IA) can be subjected to a sulphoxidation agent, for example, sodium metaperiodate or metachloroperbenzoic acid in order to obtain the compounds of formula (I) in which m=1, or to a sulphonation agent, for example, perphthalic acid or metachloroperbenzoic acid in order to obtain the compounds of formula (I) in which m=2.
The invention also relates to a preparation process for the compounds of formula (I), characterized in that a compound of formula (V): 
in which:
R17a and Rxe2x80x217a have the meanings indicated previously for R17 and Rxe2x80x217 in which the optional reactive functions are optionally protected,
X and Y have the same meaning as previously,
Rxe2x80x23 represents a hydrogen atom or a protective group of the hydroxyl function,
W represents a hydrogen atom or an acyl xe2x80x94COR radical in which R represents an alkyl radical containing 1 to 5 carbon atoms, is subjected to the,action of a compound of formula (VI):
Za-halxe2x80x2xe2x80x83xe2x80x83(VI)
xe2x80x83or a salt of the latter, in which Za has the meaning indicated previously for Z in which the optional reactive functions are optionally protected and halxe2x80x2 represents a reactive group such as a halogen or a pseudohalogen such as a mesylate or tosylate group, in the presence of a base, then if appropriate to the action of an elimination agent of the protective groups in order to obtain the compound of formula (IA) as defined above and that, if desired and if necessary, is subjected to any one of the reactions indicated for the compound of formula (IA) above.
According to this variant of the process of the invention, the compounds of formula (IA) corresponding to the compounds of formula (I) in which m=0 are obtained by reacting a compound of formula (V) in which when W is an acyl group, this can be, for example, an acetyl, propionyl, butyryl radical; ORxe2x80x23 is a hydroxyl radical optionally protected, for example, by an acetyl, tertiobutyl or tetrahydropyrannyl radical; the reactive functions that can be contained by R17a and Rxe2x80x217a are optionally protected by the usual methods, with a compound of formula (VI) or a salt of the latter, for example, a hydrochloride, the reaction being carried out in a solvent such as methanol or dimethylformamide which is optionally heated, for example, to approximately 50xc2x0 C. or under reflux and in the presence of a base such as sodium methylate or concentrated soda.
In a preferred embodiment of the invention:
the compounds of formula (V) containing a chain in position 11beta terminated by a thiol or thioacetyl group as well as the compounds of formula (VI) mentioned hereafter in the experimental part are used.
In a non-exhaustive manner, there can also be mentioned as compounds of formula (VI), either 3-chloromethylpyridine, 4-chloromethylpyridine, 6-(chloromethyl)uracile, 2-chloromethylbenzimidazole, 7-(2-chloroethyl)theophylline and the addition salts of the latter, such as hydrochloride, or iodopentane, or mesylate, tosylate or a pentafluoropentyl halide or trifluorobutyl preferably 4,4,5,5,5-pentafluoroiodopentane, 4,4,4-trifluoroiodobutane as illustrated in the examples hereafter.
The 4,4,5,5,5-pentafluoro iodopentane, whose preparation is described below in the experimental part, is obtained by the iodization of the corresponding alcohol, 4,4,5,5,5-fluoropentanol, the which product can be prepared, for example, by subjecting the corresponding partially unsaturated, 4,4,5,5,5-pentafluoro-2-penten-1-ol product, which is described by T. Kitazume et al., J. Am. Chem. Soc 1985, 107, 5186-5191, to a hydrogenation reaction, in the presence of a catalyst such as, for example, Raney nickel in methanol or platinum oxide in ethanol.
The above saturated intermediate alcohol can also be prepared according to a process described by N. O. Brace, Journal of Fluorine Chemistry 20 (1982), 313-327, starting from iodo-pentafluoroethane which is condensed under pressure with allyl alcohol, in the presence of a catalyst such as, for example, azaisobutyronitrile (AIBN), Raney nickel in ethanol, tetra kis (triphenylphosphino) palladium in hexane or tin and silver acetate in methanol in order to obtain 2-iodo-4,4,5,5,5-pentafluoropentanol which is subjected to a hydrogenation reaction, for example, by hydrogen in the presence of palladium with 10% magnesia in methanol or of Raney nickel in ethanol, or by reaction with tributyl tin hydride in the presence of azoisobutyronitrile.
The compounds of formula (IA) obtained according to the variant of the process are then, if necessary, subjected to one of the reactions indicated above, in order to obtain the compounds of formula (I).
The compounds of formula (I) have useful pharmacological properties. Study of the products on the hormonal receptors has revealed that they possess in particular a remarkable anti-estrogen activity and antiproliferative properties, as the results of the tests given hereafter show. They also possess an anti-nidatory activity.
These properties amke the compounds of formula (I) useful in controlling fertility, for example, in some forms of anovulatory sterility, in birth control, for example, as a contraceptive and notably as a post-coital pill, as well as in the treatment of hormonal-dependent carcinomas, such as, for example, mammary carcinomas and their metastases and in the treatment of benign tumors of the breast.
Therefore a subject of the invention is the products of formula (I) as medicaments.
Among the medicaments of the invention, the compounds described in the experimental part and especially the products of the examples can be mentioned in particular. Among these products, a particular subject of the invention is, as medicaments, the following compounds of formula (I):
11beta-[8-[(2-pyridinylmethyl)thio]octyl]estra-1,3,5(10)-triene-3,17beta-diol,
11beta-[4-[3-[(1-methyl 1H-imidazol-2-yl)thio]1-propynyl]phenyl]estra-1,3,5(10)-triene-3,17beta-diol,
11beta-[4-[5-[(2-furanylmethyl)thio]pentyloxy]phenyl]estra-1,3,5(10)-triene-3,17beta-diol,
11beta-[4-[5-[(2-pyridinylmethyl)sulphinyl]pentyloxy]phenyl]estra-1,3,5(10)-triene-3,17beta-diol,
11beta-[4-[5-[(3-pyridinylmethyl)sulphinyl]pentyloxy]phenyl]estra-1,3,5(10)-triene-3,17beta-diol,
11beta-[4-[6-[(4,4,5,5,5-pentafluoropentyl)sulphinyl]hexyloxy]phenyl]estra-1,3,5(10)-triene-3,17beta-diol,
11beta-[4-[5-[(4,4,5,5,5-pentafluoropentyl)sulphonyl]pentyloxy]phenyl]estra-1,3,5(10)-triene-3,17beta-diol,
11beta-[4-[5-(pentylsulphonyl]pentyloxy]phenyl]estra-1,3,5(10)-triene-3,17beta-diol,
11beta-[4-[5-[(4,4,5,5,5-pentafluoropentyl)sulphonyl]pentyloxy]phenyl]17alpha-methyl estra-1,3,5(10)-triene-3,17beta-diol.
The useful dose varies as a function of the illness to be treated and the administration route; it can vary, for example, from 1 to 100 mg per day in an adult by oral route.
The invention extends to pharmaceutical compositions containing at least one of the medicaments as defined above as active ingredient.
The compounds of formula (I) are used by digestive, parenteral or local route, for example, by percutaneous route. They can be prescribed in the form of plain or sugar-coated tablets, capsules, granules, suppositories, pessaries, injectable preparations, ointments, creams, gels, microbeads, implants, patches; which are prepared according to the usual methods.
The active ingredient or ingredients can be incorporated with excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents, preservatives.
Some of the intermediates of formula (II) or (V) are new products and therefore a subject of the invention is also the compounds of formulae (II) and (V) as defined previously.
The new intermediate compounds of formula (II) as defined previously are prepared according to an operating method an example of which is given hereafter.
In a general manner, the compounds of formula (II) can be prepared according to the following process:
either a compound of formula (VII): 
xe2x80x83in which R17a and Rxe2x80x217a have the meaning given previously, K represents an aliphatic chain containing 2 to 19 carbon atoms linked to the steroid nucleus by a methylene radical or an arylene group, is subjected,
a) to the action of an activation agent of the alcohol function, for example tosyl chloride in pyridine, or to a halide-forming agent for example carbon tetrachloride or tetrabromide in the presence of triphenylphosphine in a neutral solvent, when K is an aliphatic chain,
b) to the action of a halogenated compound of formula (VIII):
Brxe2x80x94Y-halxe2x80x83xe2x80x83(VIII)
xe2x80x83in which Y has the meaning indicated above and hal represents a halogen, in the presence of a base, when K is an arylene group,
then, in both cases, to an aromatization agent such as palladium hydroxide on magnesia in methanol or an acetyl bromide-acetic anhydride mixture, in order to obtain the compounds of formula (II) in which X represents a methylene radical and the compounds of formula (II) in which X represents an arylenoxy group respectively,
or the compound of formula (VII) as defined above is subjected first, to the above aromatization reaction then to reaction a) or b) as indicated above,
or a compound of formula (IX): 
xe2x80x83in which Rxe2x80x23, R17a and Rxe2x80x217a have the meaning given previously, Xxe2x80x2 represents an arylene group and Yxe2x80x2 represents Y as defined above containing 2 les carbon atoms at the level of the bond with the arylene group which is represented by Xxe2x80x2, is subjected to the action of an activation agent of the alcohol function, for example, carbon tetrachloride in the presence of triphenylphosphine in a neutral solvent or tosyl chloride in pyridine, in order to obtain the compounds of formula (II) in which X is an arylene group and Y is linked directly to X by an ethynylene group, which products can be subjected, if desired, to a partial or total reaction of the triple bond.
Some of the products of formula (VII) which are necessary for the implementation of the process are known products. Their preparation is described in the preparation of the products of Example 43 and Example 50, in the European Patent Application EP 384842 the content of which is incorporated in the present Application by way of reference. The new products of formula (VII) can be prepared in a similar way, for example, by following the method described in the above Patent Application.
The products of formula (IX) which are necessary for the implementation of the process are products which are prepared according to known methods, from products of formula (X): 
in which Rxe2x80x23, R17a, Rxe2x80x217a and Xxe2x80x2 have the meaning given previously.
Starting from the products of formula (X), the products of formula (IX) are obtained by reacting, for example, either paraformaldehyde in the presence of butyl and lithium chloride in a neutral solvent, when Yxe2x80x2 represents a methylene radical, or a halide of formula Rpxe2x80x94Oxe2x80x94Yxe2x80x2-Hal1 in which Hal1 is a halogen and Rp a protective group of the alcohol function in the presence of a strong base, when Yxe2x80x2 represents an aliphatic chain having at least 2 carbon atoms. Examples of such a preparation are given hereafter in the experimental part.
Some products of formula (II), in which hal represents a halogen can also be obtained directly by reacting a halide of formula Hal2xe2x80x94Yxe2x80x2-Hal1 in which Hal1 and Hal2 respectively represent a halogen, in the presence of a strong base.
Products of formula (X) are described for example in the European Patent Application EP 384842 and other products of formula (X) can be prepared in a similar way, for example, by following the method described in the preparation of Example 31 of the above Application.
The new intermediate compounds of formula (V) as defined previously are prepared according to an operating method an example of which is given hereafter.
In a general manner, the compounds of formula (V) can be prepared according to the following process:
A compound of formula (IIxe2x80x2) corresponding to the compound of formula (II) defined above in which hal represents a chlorine or bromine atom, is subjected,
either to the action of an iodation agent, for example, sodium iodide in a neutral solvent such as acetone or methylethylketone which is optionally heated under reflux, then to the action of a salt of thiocarboxylic acid of formula (XI):
Rxe2x80x94COxe2x80x94SHxe2x80x83xe2x80x83(XI)
xe2x80x83in which R has the meaning given previously, in order to obtain the compound of formula (V) in which W is an acyl radical,
or to the action of the compound of formula (XI) indicated above in order to obtain the disulphide compound of formula (XII): 
xe2x80x83in which R3, X, Y, R17a and Rxe2x80x217a have the meaning given previously, which is subjected to a reducing agent of the disulphide, for example, tri-n-butylphosphine in a neutral solvent such as an aqueous organic solvent in order to obtain the compound of formula (V) in which W is a hydrogen atom.
In addition to the following examples which illustrate the invention without, however, limiting it, the products of formula (I) in which R17 represents a hydroxyl, Rxe2x80x217 represents a hydrogen atom, m has the values 0, 1 or 2 and X, Y, Z have the values given in the table below, constitute products which can be obtained within the scope of the present invention:
in which "PHgr" has the meaning indicated previously.